The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?
This review (2018) examines the neurobiology of depression in light of the rapid fast-acting antidepressant properties of ketamine, with particular regard for the role of inhibitory and excitatory glutamate transmission. It is evident that the primary mechanism of ketamine is the induction of transient (minutes-to-hours) postsynaptic glutamate activation, which ultimately leads to a sustained (days-to-weeks) increase in synaptic formation and strength in the prefrontal cortex. However, it is unclear whether ketamine's effects on glutaminergic inhibition via extrasynaptic NMDA) receptors exert rapid or even slow antidepressant effects.
Authors
- Gerard Sanacora
- John Krystal
- Chadi Abdallah
Published
Abstract
The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission - reviewing the history of the “glutamate inhibition” and “glutamate activation” hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.
Research Summary of 'The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?'
Introduction
Abdallah and colleagues open by situating ketamine's discovery within a longer history of serendipitous psychopharmacology, noting prior unexpected findings that ultimately led to major drug classes. They highlight that a single subanesthetic dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects, an observation that stimulated interest in targeting glutamate neurotransmission for rapid-acting antidepressants (RAADs). Early efforts emphasised glutamate inhibition (either by reducing release or blocking NMDARs) because of concerns about glutamate-mediated excitotoxicity in depression, but subsequent evidence raised the contrasting possibility that transient glutamate activation underlies RAAD effects. This perspective paper aims to synthesise preclinical and clinical data to clarify that debate. Specifically, the authors review the history of the “glutamate inhibition” versus “glutamate activation” hypotheses, propose a synaptic connectivity model of chronic stress pathology (CSP), describe ketamine’s putative mechanisms, summarise clinical efficacy of candidate RAADs, present relevant human biomarker findings, and discuss current challenges and future directions for the field.
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Study Details
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- APA Citation
Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2018). The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?. Pharmacology & Therapeutics, 190, 148-158. https://doi.org/10.1016/j.pharmthera.2018.05.010
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